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Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
in Non-Small Cell Lung Cancer
Kuiper, J.L.
2016
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citation for published version (APA)
Kuiper, J. L. (2016). Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in
Non-Small Cell Lung Cancer.
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Introduction
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1
LUNG CANCER
Incidence and risk factors
Lung cancer is the leading cause of cancer-related deaths worldwide (1). In 2015, in the
Netherlands, more than 12.000 patients were diagnosed with lung cancer and almost 11.000
patients died of the disease (2). The lifetime risk of being diagnosed with cancer of the lung
is approximately 6% (3). The most important risk factor for lung cancer is smoking; 85% of
all newly diagnosed cases of lung cancer is associated with smoking (4). Yet, also in
never-smokers, lung cancer ranks the seventh cause of cancer-related mortality worldwide (5).
Geographical variations, exposure to occupational and domestic carcinogens, hormonal and
environmental factors, as well as genetic predisposition may play a role as etiologic risk factors
(6). The relatively high risk of developing lung cancer is probably also caused by stochastic
effects associated with the lifetime number of stem cell divisions of lung tissue (7).
Classification of lung cancer
Lung cancer is histologically classified according to guidelines of the World Health Organization
(WHO) (8) (Figure 1A). The predominant histological subtype of lung cancer is non-small cell
lung cancer (NSCLC); approximately 80% of lung cancer patients is diagnosed with this type
of lung cancer (9). The remaining part concerns small-cell lung cancer (SCLC) (14-18%) and
other, more rare histological subtypes (i.e., mesothelioma and neuro-endocrine tumours)
(6%) (2, 10). Among NSCLC, the predominating histological subtype is adenocarcinoma
(approximately 40 – 45%) (11). Squamous cell carcinoma is diagnosed in 25 – 31% of
NSCLC-patients and 9 – 18% of NSCLC is of the large-cell carcinoma subtype (10, 12).
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Chapter 1 Fig. 1A Fig. 1BLung cancer
NSCLC
SCLC
Adenocarcinoma Squamous cell carcinoma Large cell carcinoma
Classification based on histology Classification of lung adeno-carcinoma based on molecular genetics
Figure 1: Classification of lung cancer
Fig. 1A: Classification of lung cancer based on histology.
Fig. 1B: Classification of lung adenocarcinoma based on molecular features. The relative frequency of major driver mutations in signaling molecules in lung adenocarcinoma is shown.
NSCLC: non-small cell lung cancer. SCLC: small cell lung cancer. EGFR: epidermal growth factor receptor mutation. KRAS: Kirsten rat sarcoma. ALK: echinoderm-associated protein-like 4 (EML4) anaplastic lymphoma kinase (ALK) translocation. ROS: ROS1 rearrangement. RET: RET fusion gene. HER2: HER2 mutation. BRAF: BRAF mutation.
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Genetics in lung cancer
In lung cancer, the most prevalent mutations are found in the gene encoding the Kirsten
rat sarcoma viral oncogene homolog (KRAS)- (29%), the epidermal growth factor receptor
(EGFR)- (11%), V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF)- (2%) and human
epidermal growth factor receptor 2 (HER2)- gene (1%) (16). Rearrangements occur in the
anaplastic lymphoma kinase (ALK) gene (5%) (16), Ret proto-oncogene (RET) gene (1%) (17)
and C-Ros Oncogene 1 (ROS1) (1%) (18). Amplification has been described in HER2 (18%) (1,
19) and Hepatocyte Growth Factor Receptor MET (2-4%) (20). Nevertheless, there is a wide
variance in incidence of these mutations between geographical regions worldwide. These
oncogenic drivers occur predominantly in adenocarcinoma and existence is usually mutually
exclusive.
Epidermal growth factor receptor
The protein EGFR is a member of the HER family, one of the 20 families of transmembrane
receptor tyrosine kinases. Tyrosine kinases are enzymes that can attach phosphate groups to
other amino acids. Phosphorylation of proteins by tyrosine kinases is an important mechanism
for intracellular communication (signal transduction) and regulating cellular activity, such as
cell division.
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Chapter 1 N-‐lobe C-‐lobeATP binding cleft
Extracellular Intracellular Transmembrane TK-‐domain Exon 18 Exon 19 Exon 21 Exon 20 Exon 22 Exon 23 Exon 24 Region where relevant EGFR-‐ mutations are located
EGF-‐receptor
EGFR gene
Figure legend:
The EGF receptor.
Figure 2
Figure 2: The EGF Receptor
EGFR-mutations in cancer
Excessive signalling through the members of the HER-receptor family is associated with
several types of cancer. Mutations in EGFR have been reported in a variety of cancers,
including anal cancer, glioblastoma multiforme and lung cancer (23, 24). In lung cancer, 90%
of all EGFR-mutations are represented by mutations in two regions, often referred to as
the ‘classic’ activating EGFR-mutations (25). These mutations concern in-frame deletions in
exon 19 (usually around the amino acids Glycine-Leucine-Arginine-Glycine-Alanine (ELREA),
residues 746-750) (45 – 50%) and the Leu858Arg (L858R) substitution, resulting from a point
mutation in exon 21 (40 – 45%) (26). Classic EGFR-mutations increase the kinase activity
of the protein, thereby continuously activating the downstream pro-survival pathways in
absence of ligand-binding (27). The remaining 10% of EGFR-mutations concern so-called
‘non-classic mutations’ (or: ‘uncommon’ mutations) in exons 18 – 21.
EGFR-mutations are reported to occur almost exclusively in non-squamous NSCLC (8). 9.4%
of Caucasian NSCLC-patients and up to 47.9% of Asian NSCLC-patients carry EGFR-mutations
in their tumours (16, 28). Regardless of ethnicity and histology, clinical characteristics that are
associated with EGFR-mutations are non-smoking (14 – 56%) and female gender (20 – 62%)
(26, 29-32), however EGFR-mutations are also reported in males (1 – 19%) and smokers (3 –
14%) as well (26).
Stage, treatment options, survival and prognosis of NSCLC
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Patients with local (stage IA – IIB) and locally advanced NSCLC (IIIA) can be curatively
treated with surgery, (stereotactic) radiotherapy and/or chemotherapy. However, due
to a lack of symptoms in the early stages of disease, the vast majority of NSCLC-patients
(more than 80%) have advanced-stage disease (stage IIIB – IV) at time of first diagnosis. For
advanced-stage NSCLC patients there are currently no curative treatment options available
(4). Nonetheless, (combinations of) new treatment modalities have been investigated in
recent years and have improved treatment outcomes of subsets of advanced-stage NSCLC.
Prognosis of advanced-stage lung cancer is to some extent dependent on biological and
clinical factors, such as weight loss, histological and molecular subtype, and performance
status (PS) (34). Despite improvement in the treatment of advanced-stage NSCLC, overall
survival (OS) is still poor. Median OS after diagnosis of stage IV NSCLC adenocarcinoma is
12.6 months (35) and the five-year survival rate of unselected patients with stage IV NSCLC
is less than 5% (1). EGFR-mutated NSCLC-patients have a better prognosis compared to the
unselected NSCLC-population; for these patients a five-year survival rate of 14% has been
reported (36).
Figure 3
Figure 3: EGFR signalling pathways.
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Chapter 1Treatment of advanced stage lung cancer
Since the discovery of platinum-based chemotherapeutic agents as anti-cancer treatment
in the 1970s, these drugs have been the standard first-line treatment for advanced-stage
lung cancer (37). Until the 1990s all advanced-stage lung cancer patients were treated with a
platinum-based chemotherapeutic regimen (usually combined with etoposide). From 2000,
the distinction between SCLC and NSCLC became clinically relevant, when it was demonstrated
that specific chemotherapeutic regimens have different efficacy in SCLC and NSCLC (38).
First-line treatment with chemotherapy improves overall survival of stage IV
NSCLC-patients by 9% (39). The optimal duration of first-line platinum-based chemotherapy
is considered to be four cycles (39, 40). A two-agent regimen of cytotoxic chemotherapy
provides the optimal effect considering tumour response and overall survival compared to
one- or three-agent regimens (41). The histological subtype of NSCLC may guide the selection
of the second chemotherapeutic agent, next to the platinum-based chemotherapeutic agent.
Patients with squamous cell carcinoma should not be treated with the third-generation
chemotherapeutic agent pemetrexed, but receive a different agent (e.g. gemcitabine) (42).
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TARGETED TREATMENT OF EGFR-MUTATED NSCLC-PATIENTS
EGFR-inhibition in lung cancer
EGFR-tyrosine kinase inhibitors (TKIs) are small molecule TKIs that bind to the tyrosine kinase
domain of the EGFR. The catalytic activity of the tyrosine kinase is blocked by the competition
of these agents with adenosine triphosphate (ATP). Gefitinib (ZD1839, Iressa) and erlotinib
(OSI-774, Tarceva) bind reversibly to the EGFR and were the first EGFR-TKIs to be registered
for lung cancer treatment. The EGFR-TKI afatinib (BIBW2992, Giotrif) is a pan-HER binding
agent and was the subsequent EGFR-TKI to be registered for the treatment of lung cancer.
In 2003, the Food and Drug Administration (FDA) granted accelerated proof for gefitinib
after evaluation in previously treated NSCLC-patients in two randomized phase II trials (43,
44). Performance status (PS), histology and female gender were clinical parameters that
were associated with a response. Most frequently reported toxicities were acne-like rash
and gastro-intestinal side effects. The second TKI that received FDA-approval for treatment
of patients with advanced stage NSCLC was erlotinib, after evaluation in the randomized,
placebo-controlled, double-blind BR.21 trial (45). Retrospective subset analyses showed that
also adenocarcinoma and smoking status were associated with response to erlotinib.
A phase III trial evaluated gefitinib in previously treated NSCLC-patients (46), but no
difference in survival was detected. However, in this trial, it was suggested that
EGFR-mutations might be the predictive biomarker for response to EGFR-TKIs (47). The INTEREST
trial was the first phase III trial that demonstrated that NSCLC-patients with EGFR-mutations
had longer PFS and higher ORR when treated with gefitinib compared to docetaxel (48).
The discovery that EGFR-mutations were the biomarker for prediction of response to
EGFR-TKI treatment in 2004 (29, 30), led to the initiation of a variety of phase III randomized
trials evaluating EGFR-TKIs in EGFR-mutated NSCLC patients (Table 1). All of these trials
demonstrated the beneficial effect of EGFR-TKIs as compared to cytotoxic chemotherapy in
NSCLC-patients carrying an EGFR-mutation, in terms of prolongation of PFS and improved
response rate. Since then, first-generation EGFR-TKIs are incorporated as first-line treatment
for EGFR-mutated NSCLC-patients in international guidelines (49-51). Erlotinib is also
registered for second-line treatment of unselected NSCLC-patients, based on the results of
the BR.21 trial (45). Despite the evident effect of erlotinib and gefitinib on PFS and response
rates, a beneficial effect on overall survival has never been demonstrated which is probably
due to cross-over of patients to EGFR-TKIs after treatment with chemotherapy (52).
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Chapter 1First-line afatinib improved OS in two phase III trials for patients with a exon 19 deletion, but
not for patients with an L858R point mutation (62). However, the results of afatinib in
NSCLC-patients with acquired resistance to erlotinib or gefitinib were disappointing; response rate
was only 8.2% (63) and OS was not prolonged in a placebo-controlled study (64).
Resistance mechanisms in EGFR-TKI treatment
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Chapter 1OUTLINE OF THIS THESIS
Lung cancer is the leading cause of cancer related mortality in the Netherlands, indicating that
novel therapies and improved treatment strategies are urgently needed. Classically, treatment
decisions have been empiric and mainly based upon histology of the tumour. Over the past
decade, it has become evident that subsets of NSCLC can be further defined at the molecular
level by recurrent ‘driver’ mutations. One of such altered genes is EGFR, which is mutated
in approximately 10% of NSCLC-patients in the Netherlands (76). Importantly, targeted
small molecule inhibitors are currently available for EGFR-mutated lung cancer patients and
have become the standard of treatment for these patients. The introduction of these
first-generation EGFR-TKIs in the treatment of lung cancer has been a major step forward, yet
new challenges and questions have arisen as well. This thesis describes the results of clinical
studies conducted among EGFR-mutated NSCLC-patients and NSCLC-patients with acquired
resistance to first-generation EGFR-TKIs. The first part focuses on diagnostics and predictive
markers, and the second part focuses on treatment.
Diagnostics & response prediction
Prevalence of uncommon EGFR-mutations
Studies that report on non-classic EGFR-mutations are limited and data on EGFR-TKI
sensitivity of these mutations is scarce, especially in non-Asian populations. In Chapter 2, we
describe the prevalence and type distribution of non-classic EGFR-mutations among Dutch
EGFR-mutated NSCLC-patients, as well as clinical characteristics and outcomes on EGFR-TKI
treatment in this cohort.
T790M mutation as mechanism of EGFR-TKI-resistance
The T790M mutation is the most frequently detected mechanism of resistance in
EGFR-mutated NSCLC-patients after having acquired resistance to EGFR-TKI treatment. The
mutation is rarely found independently of EGFR-TKI treatment, however some patients in
whom the T790M mutation was detected prior to EGFR-TKI treatment have been reported
(77). Heterogeneity of T790M detection has been described in individual cases, both in time
(78) and between different tumour lesions (79). In Chapter 3, we describe the occurrence
of T790M mutations in a cohort of EGFR-mutated NSCLC patients who were rebiopsied after
having acquired EGFR-TKI-resistance.
Histological transformation and tumour heterogeneity
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has gained interest given its likely role in the development of resistance to treatment. In
Chapter 4a, we describe an EGFR-mutated NSCLC-patient in whom an innovative PET imaging
method was used that could possibly play a role in detecting tumour heterogeneity in the
future.
Histological transformation after treatment with EGFR-TKIs, e.g. transformation from
NSCLC to SCLC, has been described as resistance mechanism, but is infrequently reported
(67). Histological transformation may develop as a result of tumour heterogeneity that was
present prior to treatment initiation. In Chapter 4b we describe a patient who was rebiopsied
after acquired resistance to EGFR-TKI treatment and in whom a different form of histologic
transformation after EGFR-TKI treatment was reported; transition of an adenocarcinoma to
squamous cell carcinoma phenotype.
Serum-based proteomic biomarkers
Although the presence of an EGFR-mutation in the tumour is predictive for response on
EGFR-TKI treatment, some EGFR-wild type (WT) patients experience prolongation of PFS
when treated with EGFR-TKI treatment (45). Moreover, in some patients assessment of
tumour mutation-status is either not possible or it is not possible to obtain (new)
tumour-tissue. Therefore, it would be helpful to have a less-invasive biomarker test available that is
predictive for response to EGFR-TKI treatment.
VeriStrat is a serum-based proteomic test that is commercially available in the United
States and has shown to predict outcome after treatment with EGFR-TKIs (81-85). Chapter 5
describes the results of the VeriStrat-test in a cohort of unselected NSCLC-patients who were
treated with the combination of erlotinib and sorafenib.
Treatment
Present-day challenges in EGFR-TKI-resistant NSCLC
Since two decennia, response to anti-cancer treatment is measured according to the response
evaluation criteria in solid tumors (RECIST) (86). One of the important issues is whether
traditional response evaluation criteria are still applicable in the treatment with targeted
agents. This issue is reviewed in Chapter 6, as well as the mechanisms of resistance and
different treatment strategies in EGFR-mutated NSCLC with acquired EGFR-TKI resistance.
Leptomeningeal metastases
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Chapter 1the compartment of the cerebrospinal fluid (89). It is considered to be a complication with
poor prognosis and rapid deterioration of performance status (90). In Chapter 7, we describe
diagnosis, treatment and survival of EGFR-mutated NSCLC-patients with leptomeningeal
metastases.
Pulsatile EGFR-TKI treatment
It is believed that, due to the blood-brain barrier (BBB), EGFR-TKIs do not reach therapeutic
concentrations in the intra-central nervous system (CNS) compartment when administered
in standard dose (91). It is hypothesized that with high-dose weekly erlotinib, therapeutic
concentrations in the intra-CNS fluid can be reached (92). In Chapter 8a, we describe
two EGFR-mutated NSCLC-patients who developed leptomeningeal metastases and both
responded to high-dose EGFR-TKI treatment. Interestingly, one patient also had a response
of the intrathoracic lesions that had been resistant for previous chemotherapy.
Since EGFR-TKIs are competitive inhibitors of EGF signalling, it can be hypothesized that
higher doses of the drug might restore the sensitivity. The results of a phase II trial that
evaluated high-dose weekly EGFR-TKI treatment in EGFR-mutated NSCLC-patients who
acquired resistance to standard-dose EGFR-TKI treatment, are described in Chapter 8b.
Afatinib
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